eNOS-Dependent Antisenscence Effect of a Calcium Channel Blocker in Human Endothelial Cells

Abstract

Senescence of vascular endothelial cells is an important contributor to the pathogenesis of age-associated vascular disorders such as atherosclerosis. We investigated the effects of antihypertensive agents on high glucose-induced cellular senescence in human umbilical venous endothelial cells (HUVECs). Exposure of HUVECs to high glucose (22 mM) for 3 days increased senescence-associated- β-galactosidase (SA-β-gal) activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker. The calcium channel blocker nifedipine, but not the β1-adrenergic blocking agent atenolol or the angiotensin-converting enzyme inhibitor perindopril, reduced SA-β-gal positive cells and prevented a decrease in telomerase activity in a high-glucose environment. This beneficial effect of nifedipine was associated with reduced reactive oxygen species (ROS) and increased endothelial nitric oxide synthase (eNOS) activity. Thus, nifedipine prevented high glucose-induced ROS generation and increased basal eNOS phosphorylation level at Ser-1177. Treatment with N G-nitro-L-arginine (L-NAME) and transfection of small interfering RNA (siRNA) targeting eNOS eliminated the anti-senscence effect of nifedipine. These results demonstrate that nifedipine can prevent endothelial cell senescence in an eNOS-dependent manner. The anti-senescence action of nifedipine may represent a novel mechanism by which it protects against atherosclerosis.

The role of cold‐inducible RNA binding protein in cell stress response

“…It is noteworthy that reducing temperature also increases the level of dissolved oxygen concentration, which may cause the hypoxic response and follow by changing the level of reactive oxygen species (ROS). ROS are products of cellular metabolism including superoxide anions and hydroxyl radicals . As second messengers, normal levels of cellular ROS participate in signal transduction pathways, while their abnormal accumulation impacts intracellular macromolecules and induces cumulative damage at cellular, tissue and organismal levels .…”

Blood pressure normalization via pharmacotherapy improves cutaneous microvascular function through NO‐dependent and NO‐independent mechanisms

“…Of those taking multiple antihypertensive medications, three were co‐prescribed diuretics, which do not alter endothelial function or vessel structure . The final subject was co‐prescribed a calcium channel blocker, which has been shown to exert effects on the endothelium . Unmedicated essential hypertensive and normotensive control subjects were not taking any antihypertensive medications.…”

“…10,46 The final subject was co-prescribed a calcium channel blocker, which has been shown to exert effects on the endothelium. 47 Unmedicated essential hypertensive and normotensive control subjects were not taking any antihypertensive medications. All subjects were free of other, non-antihypertensive medications which could alter blood flow.…”

Membrane ion Channels and Receptors in Animal lifespan Modulation

“…The dysfunctions of calcium channels may also contribute to the age‐related vascular disorders since calcium channel blockers are commonly used to treat hypertension in the elderly (Caballero‐Gonzalez, ). For instance, the calcium channel blocker nifedipine can delay senescence and prevent telomerase activity decline in human endothelial cells (Hayashi et al, ). These anti‐senescence effects are likely achieved by reducing the production of ROS and enhancing the activity of nitric oxide synthase (eNOS) (Hayashi et al, ).…”

“…For instance, the calcium channel blocker nifedipine can delay senescence and prevent telomerase activity decline in human endothelial cells (Hayashi et al, ). These anti‐senescence effects are likely achieved by reducing the production of ROS and enhancing the activity of nitric oxide synthase (eNOS) (Hayashi et al, ).…”